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Protein Imbalance in Akt Pathway May Trigger Cancer

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Key Points

  • Two proteins—Plcγ1 and Grb2—compete for binding to FGFR2, a cell wall–bound receptor. When Plcγ1 prevails, it triggers the Akt pathway, causing uncontrolled cell proliferation.
  • Grb2 depletion results in the development of multiple tumors in the vicinity of a primary tumor, indicating that protein imbalance can have a role in metastasis.
  • A high level of Grb2 relative to Plcγ1 and FGFR2 in ovarian cancer was associated with a significantly more favorable prognosis than elevated levels of Plcγ1.

Cancer can be caused solely by protein imbalance within cells, a study of ovarian cancer has found. Until now, genetic aberrations have been seen as the main cause of almost all cancer. The research, published by Timsah et al in Oncogene, demonstrates that protein imbalance is a powerful prognostic tool, indicating whether or not patients are likely to respond to chemotherapy and whether a tumor is likely to spread to other sites. The findings also open the possibility of new therapies aimed at measuring and preventing dangerous imbalances in cells.

John Ladbury, PhD, MSc, BSc, Dean of the University of Leeds’ Faculty of Biological Sciences and Professor of Mechanistic Biology, said, “There has been huge investment in sequencing the human genome, with the idea that if we get all the relevant genetic information, we can predict whether you have a predisposition to cancer and, ultimately, use a precision medicine-based approach to develop a therapeutic approach. Our study demonstrates that genetic screening alone is not enough.”

Akt Pathway

The research, led by scientists at the University of Leeds and The University of Texas MD Anderson Cancer Center, focused on the Akt pathway, a signaling pathway within cells that drives cancer formation and metastasis.

Under normal conditions, the cell receives external signals through a cell wall–bound receptor (FGFR2 in this study). As a result of this stimulus, the receptor is “switched on” inside the cell. This results in the recruitment of signaling proteins and the initiation of the Akt pathway, which is responsible for committing the cell to proliferate. In some cancerous cells, this pathway is permanently switched on.

A conventional approach to diagnosing this cancer would be to look for genetic modification of the receptor (or recruited proteins), which could be responsible for maintaining the switched-on state.

Binding and Proliferation of Cancer Cells

The new study looked at isolated cancer cells without external stimulation and found that the Akt pathway could be activated without genetic modifications. Two proteins—Plcγ1 and Grb2—compete for binding to FGFR2. The relative concentration of these proteins will dictate which one binds. When Plcγ1 prevails, it triggers the Akt pathway. In this way, an imbalance in the amount of the two proteins can lead to cell proliferation and cancer formation.

Dr. Zahra Timsah, University Academic Fellow at the University of Leeds' School of Molecular and Cellular Biology, said, “This competition for binding to the receptor represents an unexpected way in which cancer can occur. We found that in cells where Grb2 is depleted, FGFR2 was vulnerable to Plcγ1 binding, and that this triggered uncontrolled proliferation. Increasing the amount of Grb2 rescued this effect to maintain normal FGFR2 activity. What we think is happening is that, under normal conditions, the two proteins compete fairly evenly. Plcγ1 binding events allow useful cell housekeeping. When the proteins get imbalanced, Plcγ1 can get out of control.”

The researchers also looked at the process in a mouse model and found that Grb2 depletion results in the development of multiple tumors in the vicinity of a primary tumor, indicating that protein imbalance can have a role in metastasis.

Proteins as Biomarkers

Finally, the researchers looked at whether imbalance between Grb2 and Plcγ1 was predictive of the progress of ovarian cancer in patients. Measuring the levels of the proteins in patient tissues, followed by database analysis of clinical information from The Cancer Genome Atlas and other sources, revealed that a high level of Grb2 relative to Plcγ1 and FGFR2 was associated with a significantly more favorable prognosis than elevated levels of Plcγ1.

Statistical data reveal that just fewer than 40% of patients with a favorable balance were still alive 7 years after samples were taken. Less than 10% of patients with high levels of Plcγ1 and FGFR2 binding sites survived the same length of time.

Dr. Ladbury said, “From the patient's point of view, the key findings are that these proteins are biomarkers. They could offer information to clinicians on who is going to benefit from therapy and, just as importantly, who is not. On the treatment side, the proteins' interaction could be a valid therapeutic target: you could, for instance, target Plcγ1 to ensure it does not overwhelm the cell.”

Previous research findings have emphasized the roots of cancer in genetic mutation. Some studies have pointed to cancers that occur without genetic causes, such as through epigenetic modifications of proteins. However, the present study reveals that signaling through cell wall–based receptors can occur without receptor activation, and therefore, that nongenetic causes may be critical to understanding cancer in large numbers of patients.

The researchers are now working with clinicians at the University of Leeds to study the same mechanisms in other forms of cancer. They are also exploring the possibility that other cell receptors could play a similar role to FGFR2 in sustaining oncogenic signaling without being activated.

This study was supported by the G. Harold and Leila Y. Mathers Charitable Foundation, the National Institutes of Health, the RGK Foundation, and the Gilder Foundation. 

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


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